Desformoterol and process for its preparation

ABSTRACT

The (R,R)-, (S,S)-, (R,S)-, (R,S)- isomers of 3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]-benzenemethanol (D) ##STR1## are disclosed, as well as an efficient method for their stereoselective synthesis. A method and composition are also disclosed utilizing desformoterol (D) as a bronchodilator, having high selectivity for β 2  receptors.

FIELD OF THE INVENTION

The present invention relates to 3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]benzenemethanol, to pharmaceuticalcompositions thereof and to its use in treating and preventing pulmonarydisorders. The invention further relates to optically pure isomers of3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]-benzenemethanol and a process for theirpreparation.

BACKGROUND OF THE INVENTION

Formoterol, (+/-)N-[2-hydroxy-5-[1-hydroxy-2 [[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phenyl]-formamide, is a highly potent andβ₂ -selective adrenoceptor agonist having a long lasting bronchodilatingeffect when inhaled. The structure of formoterol is as shown: ##STR2##

Formoterol has two chiral centers in the molecule, each of which canexist in two possible configurations. This gives rise to fourcombinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirrorimages of each other and are therefore enantiomers; (R,S) and (S,R) aresimilarly an enantiomeric pair. The mirror images of (R,R) and (S,S) arenot, however, superimposable on (R,S) and (S,R), which arediastereomers. Formoterol is available commercially only as a racemicmixture (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterolrefers to this enantiomeric mixture.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines indicatedisavowal of any stereochemical implication which the bond it representscould generate; solid and broken bold lines are geometric descriptorsindicating the relative configuration shown but denoting racemiccharacter; and wedge outlines and dotted or broken lines denoteenantiomerically pure compounds of indeterminate absolute configuration.Thus, the formula for formoterol above reflects the racemic nature ofthe commercial material, while among the structures below, those havingopen wedges are intended to encompass both of the pure enantiomers ofthat pair and those having solid wedges are intended to encompass thesingle, pure enantiomer having the absolute stereochemistry shown.

    ______________________________________                                        Representation of Bonds to Chiral Carbons According to Maehr                                Stereochemical                                                    Symbol Significance                                                         ______________________________________                                                  1  Optically pure - Indeterminate Configuration                     2  Racemic - but having the relative configuration shown                         -                                                                          3  Chiral - Absolute Configuration                                               -                                                                          4  No Stereochemistry Indicated                                               ______________________________________                                    

The synthesis of the four stereoisomers of formoterol has been reportedin the literature. In one method, the (R,R)- and (S,S)- isomers wereisolated by stereoselective crystallization of racemic formoterol withoptically pure tartaric acid (Murase et al., Chem. Pharm. Bull. 26,1123-1129 (1978)). In another method, racemic 4-benzyloxy-3-nitrostyreneoxide was coupled with an optically pure (R,R)- or(S,S)-N-(1-phenylethyl)-N-(1-(p-methoxyphenyl)-2-propyl)amine to give adiastereomeric mixture of formoterol precursors, which were thenseparated by semipreparative HPLC and transformed to the pure formoterolisomers (Trofast et al., Chirality 3, 443-450 (1991)). Both methodssuffer from very low yields (<2%) and long synthetic procedures.

3-Amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]-benzenemethanol(Chem. Abst. Reg. No. 150513-24-9) has been disclosed as an undesiredside product in a synthesis of formoterol (Spanish Patent ES 2031407).Its structure is shown below. ##STR7## Neither its deliberate synthesisnor its pharmacology has been previously reported.

SUMMARY OF THE INVENTION

It has now been discovered that3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]benzenemethanol(I) is also a highly selective β₂ -adrenergic receptor agonist. Theprocesses of the invention provide a practical, efficient method forpreparing the compound, and also provide a synthesis of all of its fourstereoisomers with high optical purity.

The compounds, methods and compositions of the invention relate to3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]benzenemethanoland to stereoisomers thereof. For simplicity's sake,3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]benzenemethanolwill henceforth be referred to as "desformoterol." Throughout theinstant disclosure, when the term is not otherwise modified,"desformoterol" indicates the R,R-isomer, the S,S-isomer, theR,S-isomer, the S,R-isomer or any mixture of these stereoisomers. Theterm "racemic desformoterol" includes the two possible racemates, one amixture of the R,R- and the S,S-isomers, and the other, a mixture of theR,S- and the S,R-isomers.

In one aspect, the invention relates to a process for preparing acompound of formula: ##STR8## comprising providing a compound offormula; ##STR9## and reducing said compound. The compound of formula##STR10## is prepared by reacting a compound of formula ##STR11## with acompound of formula ##STR12## wherein R is benzyl or substituted benzyl.

Similarly, the invention relates to a process for preparing a salt of anoptically pure compound of formula: ##STR13## by providing a compound offormula ##STR14## and reducing said compound in the presence of an acid.The compound of formula ##STR15## is prepared by reacting a compound offormula ##STR16## with a compound of formula ##STR17## wherein R isbenzyl or substituted benzyl.

The term "substituted benzyl" refers to any protecting group for aphenol that contains the benzyl (or phenylmethyl) nucleus substitutedwith one or more substituents that do not interfere with its function asa protecting group. Suitable substituents include: C₁ to C₆ -alkyl, C₁to C₆ -alkoxyl, halogen and combinations thereof. In a particularembodiment, R is benzyl, represented herein as Bn.

In the foregoing processes the reducing step is carried out with asource of hydrogen in the presence of a noble metal catalyst. Apreferred noble metal catalyst is palladium. It is further preferredthat the reducing step be carried out in the presence of tartaric acidin addition to the catalyst. The source of hydrogen may be hydrogen gasor a hydrogen-donating compound such as ammonium formate.

Suitable acid addition salts for the compounds of the present inventioninclude for example, acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. Themandelic acid salt is especially preferred for benzylamine compounds;the tartrate is preferred for desformoterol stereoisomers.

The present invention also includes novel compositions of matter,containing desformoterol, which are useful as bronchodilators for therelief of reversible bronchospasm in patients with obstructive airwaydisease such as asthma, bronchitis and emphysema.

In one aspect the invention relates to methods of inducingbronchodilation or preventing bronchoconstriction with desformoterolcomprising administering to an individual a quantity of desformoterolsufficient to induce bronchodilation or prevent bronchoconstriction. Thedesformoterol may be administered orally or by subcutaneous injection,intravenous infusion, inhalation, or transdermal delivery. Inhalation ispreferred. The amount administered by inhalation is about 1 μg to about100 μg per day, in single or divided doses.

In another aspect, the invention relates to compositions for oraladministration, including syrups and unit dosage forms, such as tabletsand capsules, or formulations suitable for administration by inhalation,e.g. solution or suspension in a suitable propellant for use in ametered-dose inhaler or sterile aqueous solution for nebulization. Thecompositions comprise a pharmaceutically acceptable propellant (foraerosols) or carrier (for inhalation solutions, syrups, tablets andcapsules) and desformoterol or a pharmaceutically acceptable saltthereof. A preferred bronchodilator composition is in the form of anaerosol formulation.

DETAILED DESCRIPTION

In one aspect, the present invention relates to a practical andefficient process for the preparation of desformoterol and opticallypure isomers. This method is particularly advantageous because itutilizes optically pure precursors that are readily available by simpleresolution and asymmetric reduction. Mixtures of enantiomers ofdesformoterol may be prepared conveniently by starting with materialswhich are not optically pure.

The overall sequence is set forth in Scheme 1, wherein R has beenexemplified as benzyl, represented as Bn. The scheme illustrates theprocedure for the synthesis of optically pure products, but the sameprocedure is useful for preparing mixtures of isomers. The sequencecould also be used to produce other intermediates in which R issubstituted benzyl by beginning with the appropriate starting materialanalogous to 2. Brackets indicate intermediates that could be isolatedbut may not be isolated in the integrated process. ##STR18##

In the process described above, the optically pure4-methoxy-α-methyl-N-(phenylmethyl)benzene ethanamine, also called2-N-benzylamino-1-(p-methoxyphenyl)propane 4, is obtained by resolutionof the racemic compound with L- or (D)-mandelic acid using amodification of the procedure of Kraft, et al. [Rec. Trav. Chim.Pays-Bas 85, 607 (1966)]. The racemic N-benzylamine compound wasprepared by the reductive amination of p-methoxyphenylacetone withN-benzylamine under catalytic hydrogenation, but other reductiveconditions using methods known in the art could be used. (See,Houben-Weyl's Methoden der Org. Chem. Band IV/1c, p427.)

The invention encompasses a process for making optically puredesformoterol from optically pure 4-benzyloxy-3-nitrostyrene oxide 1comprising the coupling and hydrogenation described above in combinationwith a method for the preparation of the optically pure styrene oxides.According to this aspect the optically pure styrene oxide is obtainedby: (a) reduction of 2'-bromo4-benzyloxy-3-nitroacetophenone with boranestereoselectively in the presence of a chiral oxazaborolidine catalystto give the corresponding optically active bromohydrin [See Hong, etal., Tetrahedron Lett. 35, 6631(1994) and U.S. Pat. No. 5,495,821, thedisclosures of which are incorporated herein by reference]; and (b)conversion of the 3-nitro-bromohydrin to the corresponding4-benzyloxy-3-nitrostyrene oxide 1 with a base.

The optically pure 2-N-benzylamino- 1-(p-methoxyphenyl)propane 4 isobtained by resolution of the racemic compound with L- or D-mandelicacid. The resolution of the racemic N-benzylamine compound is performedusing one equivalent of L- or D-mandelic acid in an alcohol solvent suchas methanol (MeOH). The optically pure benzylamine mandelic acid salt 3is obtained after four or five crystallizations. The free N-benzylaminecompound is then obtained by treating the mandelic acid salt with a basesuch as aq. NaOH or aq. Na₂ CO₃ or aq. NH₃ in the presence of an inertorganic solvent such as t-butyl methyl ether (MTBE) or ethyl acetate(EtOAc) followed by evaporation of the solvent.(R)-2-N-benzylamino-1-(p-methoxyphenyl)propane is obtained from theL-(+)-mandelic acid salt while the (S)-enantiomer is obtained from theD-(-)-mandelic acid salt. From the same lot of racemic N-benzylaminecompound, both (R)- and (S)-enantiomer can be obtained by using theappropriate mandelic acid.

The optically pure epoxide 1 is prepared from commercially available4-benzyloxy-3-nitroacetophenone. Thus, the acetophenone may bebrominated with bromine in an inert organic solvent such as CH₃ CN, MeOHor chloroform to give the α-bromoacetophenone. The bromoacetophenone isthen reduced with a borane reducing agent such as BH₃.THF or BH₃.Me₂ Sin the presence of a chiral oxazaborolidine catalyst to give theoptically active bromohydrin by extraction from aqueous acid inexcellent yield (>98%) and good enantiomeric excess (ee=95%). An exampleof such a catalyst is cis-(1R,2S)-aminoindanol-B-Me, or AIBMe, which isthe product of the reaction between cis-(1R,2S)-aminoindanol andtrimethylboroxine, according to the procedure described in U.S. Pat. No.5,495,821. The bromohydrin can be further enriched to >99.8% ee bycrystallization. The absolute configuration of the bromohydrin isdetermined by the chirality of the oxazaborolidine catalyst. Theresulting compound is converted to optically pure4-benzyloxy-3-nitrostyrene oxide with a base such as aq. NaOH or K₂ CO₃in an alcohol solvent or solvent mixture such as MeOH/THF. The epoxidecan be isolated by extraction of the reaction mixture with ethylacetate/water, drying the organic phase and evaporating the solvent.

Epoxide formation from bromohydrin 2 and release of the free base frombenzylamine 3 may be accomplished in separate steps or in a single step.The optically pure 2-N-benzylamino-1-(p-methoxyphenyl) propane 4 isreacted with optically pure 4-benzyloxy-1-nitrostyrene oxide 1 withoutracemization to give an optically pure N,O-di-benzyldesformoterolintermediate 5, and the N,O-dibenzyl groups of thedibenzyl-desformoterol are removed by hydrogenation in the presence of ahydrogenation catalyst, to give optically pure desformoterol. However,since both reactions require a base, a combination of both steps into aone-pot procedure is possible and simplifies the process. Under thisscheme, the dibenzyl-desformoterol is obtained directly from thereaction of optically pure 2-N-benzylamino-1-(p-methoxyphenyl) propane 3with the optically pure 1-(4'-benzyloxy-3'-nitrophenyl)-2-bromoethanol 2in the presence of a base whereby the epoxide 1 is formed in situ.

The condensation of the N-benzylamine sidechain with the epoxide may becarried out without solvent at temperature in the range of 100-140° C.,or in a high boiling inert solvent under reflux. Suitable solventsinclude toluene, t-butanol, t-amyl alcohol, and methyl isobutylketone(MIBK). The resulting dibenzyldesformoterol 5 can be purified by columnchromatography. It can also be used directly without purification forthe de-benzylation reaction to form desformoterol.

The dibenzyldesformoterol product is converted by catalytichydrogenation in the presence of Pd catalyst such as Pd/C directly todesformoterol. The hydrogenolysis is preferably performed on a saltformed from an appropriate organic acid, in an alcohol solvent such asmethanol, ethanol, or 2-propanol, at 40-60 psi of hydrogen pressure andat a temperature of 15-30° C. for 2-15 hours.

The resulting desformoterol acid salt is then isolated by removing thesolvent after filtration to remove the catalyst. The acid may be presentin any ratio, but one equivalent is optimal with non-volatile acids, inthat the salt is directly isolated from the reaction. Employing a ratiogreater than one is generally unnecessary and a ratio less than oneresults in slower hydrogenolysis and a need to further manipulate theproduct to obtain either the free base or a pure salt.

It has been observed that the stability of desformoterol can varyaccording to conditions. The compound exhibits maximum stability in anenvironment maintained at a pH of 2.

Binding studies of desformoterol and individual diasteromers have shownthat the racemate and the R,R stereoisomer are highly selectiveβ-adrenergic receptor agonists. The four isomers of desformoterol,(R,R)-, (S,S)-, (R,S)-, and (S,R)-, and a 1:1 mixture of the (R,R)- andthe (S,S)-enantiomers, were screened, in duplicate, at threeconcentrations (10⁻⁹, 10⁻⁷, 10⁻⁵ M) for binding to human β₁ and β₂-adrenergetic receptors. The compounds were then tested at tenconcentrations in duplicate in order to obtain full competition curves.Reference compounds were simultaneously tested at eight concentrations.IC₅₀ values (concentration required to inhibit 50% of specific binding)were then determined by nonlinear regression analysis. Results aretabulated below.

                  TABLE 1                                                         ______________________________________                                                    IC.sub.50 (nM)                                                    COMPOUND      β.sub.1                                                                            β.sub.2                                                                         β.sub.1 /β.sub.2 Selectivity         ______________________________________                                        (R,R)-Desformoterol                                                                         3,180     35.6   89                                               Atenolol 1,200 -- --                                                          ICI 118551 --  2.5 --                                                       ______________________________________                                    

(R,R)-desformoterol displayed significant binding primarily at the β₂-site and its selectivity (β₁ /β₂) for the β₂ -receptor wasapproximately 89-fold.

                  TABLE 2                                                         ______________________________________                                                    IC.sub.50 (nM)                                                    COMPOUND      β.sub.1                                                                            β.sub.2                                                                         β.sub.1 /β.sub.2 Selectivity         ______________________________________                                        (R,S)-Desformoterol                                                                         1,790     3,140  <1                                               (S,R)-Desformoterol - 1,890 --                                              Atenolol      1,430     --     --                                             ICI 118551    --        2.4    --                                             ______________________________________                                    

Neither (R,S)- nor (S,R)-desformoterol showed high affinity for the β₁receptor. The binding of (R,S)-desformoterol was comparable to that ofatenolol at the β₁ -site, and an IC₅₀ was not determined for(S,R)-desformoterol because only 22% inhibition was attained at 10⁻⁵ M.

                  TABLE 3                                                         ______________________________________                                                   IC.sub.50 (nM)                                                     COMPOUND     β.sub.1                                                                            β.sub.2                                                                           β.sub.1 /β.sub.2 Selectivity        ______________________________________                                        (R,R)-/(S,S)-Racemate of                                                                   5,142     81.3     63                                              Desformoterol                                                                 (S,S)-Desformoterol 64,710  >10,000 <6                                      Atenolol     1,300     --       --                                            ICI 118551   --        1.9      --                                            ______________________________________                                    

Not surprisingly, the (R,R)/(S,S) racemate of desformoterol displayedsignificant binding only at the β₂ -site, since it is a mixture of equalparts of the (R,R)- and (S,S)- enantiomers, and (S,S)-desformoterollacked affinity for both β-adrenergic sites.

The present invention also encompasses a method of inducing abronchodilation effect or preventing bronchoconstriction which comprisesadministering to a human in need of bronchodilation an amount ofdesformoterol or a pharmaceutically acceptable salt thereof sufficientto alleviate bronchospasms. Inducing bronchodilation and preventingbronchoconstriction provide relief from the symptoms associated withobstructive airway diseases, e.g., asthma or chronic obstructivepulmonary disease (COPD) which include but are not limited torespiratory distress, wheezing, coughing, shortness of breath, tightnessor pressure in the chest and the like.

The present invention additionally encompasses a pharmaceuticalcomposition for the treatment of a patient in need of bronchodilatingtherapy which comprises desformoterol or a pharmaceutically acceptablesalt thereof. The desformoterol may be a single optically purestereoisomer of a mixture thereof. The term "optically purestereoisomer" as used herein means that the composition contains atleast about 90% by weight of a specific stereoisomer of desformoterol,that is, one of (R,R), (S,S), (R,S) or (S,R), and 10% or less by weightof any combination of other stereoisomers of desformoterol. In a morepreferred embodiment the composition contains at least 99% by weight ofa single stereoisomer of desformoterol and 1% or less of otherstereoisomers. In the most preferred embodiment the composition containsgreater than 99% by weight of a single stereoisomer of desformoterol andless than 1% by weight of other stereoisomers.

The magnitude of a prophylactic or therapeutic dose of desformoterol inthe acute or chronic management of disease will vary with the severityof the condition to be treated, and the route of administration. Thedose, and perhaps the dose frequency, will also vary according to theage, body weight, and response of the individual patient. In general,the total daily dose ranges when administered by inhalation, for theconditions described herein, is from about 1 μg to about 100 μg, insingle or divided doses. Preferably, a daily dose range should bebetween about 6 μg to about 25 μg, in single or divided doses, in fromtwo to four divided doses. In managing the patient, the therapy shouldbe initiated at a lower dose, perhaps about 3 μg to about 12 μg, andincreased up to about 2×12 μg or higher depending on the patient'sglobal response. When administered orally, preferably as a tablet, thepreferred dose range is from 0.1 to 1.0 mg per day. It is furtherrecommended that children, and patients over 65 years, and those withimpaired renal, or hepatic function, initially receive low doses, andthat they be titrated based on individual responses and blood levels. Itmay be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician would know how and when tointerrupt, adjust, or terminate therapy in conjunction with individualpatient response. The terms "an amount sufficient to alleviatebronchospasms," "an amount sufficient to prevent bronchoconstruction"and "a therapeutically effective amount" are encompassed by theabove-described dosage amounts and dose frequency schedule.

The pharmaceutical compositions of the present invention comprise as theactive ingredient desformoterol thereof or a pharmaceutically acceptablesalt thereof, and may also contain a pharmaceutically acceptablecarrier, and optionally, other therapeutic ingredients. The term"pharmaceutically acceptable salts" or "a pharmaceutically acceptablesalt thereof" refer to salts prepared from pharmaceutically acceptablenontoxic acids including inorganic acids and organic acids. Suitablepharmaceutically acceptable acid addition salts for the compound of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Thetartaric acid salt is particularly preferred.

Preferred unit dosage formulations are those containing an effectivedose, as recited, or an appropriate fraction thereof, of the activeingredients particularly mentioned above. The formulations of thisinvention may include other agents conventional in the art having regardto the type of formulation in question. For example, formulations fororal administration may include carriers such as starches, sugars,microcystalline cellulose, diluents, granulating agents, flavoringagents and the like. The compositions include formulations suitable fororal, rectal and parenteral administration (including subcutaneous,transdermal, intramuscular, and intravenous) and inhalation.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of desformoterol. For example, oral,rectal, parenteral (subcutaneous, intramuscular, intravenous),transdermal, and like forms of administration may be employed. Dosageforms include tablets, troches, dispersions, suspensions, solutions,capsules, patches, syrups, and the like. Oral and parenteral sustainedrelease dosage forms may also be used.

Oral syrups, as well as other oral liquid formulations, are well knownto those skilled in the art, and general methods for preparing them arefound in any standard pharmacy school textbook, for example Remington:The Science and Practice of Pharmacy. Chapter 86 of the 19th edition ofRemington entitled "Solutions, Emulsions, Suspensions and Extracts"describes in complete detail the preparation of syrups (pages 1503-1505)and other oral liquids. Similarly, sustained release formulation is wellknown in the art, and Chapter 94 of the same reference, entitled"Sustained-Release Drug Delivery Systems," describes the more commontypes of oral and parenteral sustained-release dosage forms (pages1660-1675.) The relevant disclosure, Chapters 84 and 96, is incorporatedherein by reference.

The most preferred route of administration of the present invention isinhalation. Formulations suitable for inhalation include sterilesolutions for nebulization comprising a therapeutically effective amountof desformoterol, or a pharmaceutically acceptable salt thereof,dissolved in aqueous saline solution and optionally containing apreservative such as benzalkonium chloride or chlorobutanol, and aerosolformulations comprising a therapeutically effective amount ofdesfornoterol, or a pharmaceutically acceptable salt thereof, dissolvedor suspended in an appropriate propellant (e.g., HFA-134a, HFA-227, or amixture thereof, or a chlorofluorocarbon propellant such as a mixture ofPropellants 11, 12 and/or 114) optionally containing a surfactant.Aerosols may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the art of pharmacy. The preparationof a particularly desirable aerosol formulation is described in EuropeanPatent No. 556239, the disclosure of which is incorporated herein byreference. Also suitable are dry powder formulations comprising atherapeutically effective amount of desformoterol, or a pharmaceuticallyacceptable salt thereof, blended with an appropriate carrier and adaptedfor use in connection with a dry-powder inhaler.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compounds, thepharmacological characterization thereof, and the preparation ofcompositions of the present invention. It will be apparent to thoseskilled in the art, that many modifications, both to materials, andmethods, may be practiced without departing from this invention.

EXAMPLE 1 2-Bromo-4'-benzyloxy-3'-nitroacetophenone

A 5-liter flask was charged with 300 g (1.1 mol) of4-benzyloxy-3-nitroacetophenone and 3 liters of acetonitrile. Themixture was heated to 50° C. to form a clear solution, and 180 g ofbromine (1.6 mol) was added in one portion. The reaction was stirred at50° for 15-25 minutes, during which time the deep red color changed topale orange and TLC (ethyl acetate/hexane 3:7) showed no remainingstarting material. Without heating, 200 to 300 mL of acetonitrile, alongwith the byproduct hydrogen bromide, were distilled from the reactionunder vacuum. During the course of the distillation, the temperaturedropped to about 15° and the product precipitated as a yellow solid. Thereaction was stirred at 0-5° for two hours and the product was filteredoff and washed with acetonitrile. The resulting 2-bromo4'-benzyloxy-3'-nitroacetophenone was dried in vacuum to yield 242 g(63%) of an off-white solid having a melting point of 136° C.

EXAMPLE 2 R-2-Bromo-1-((4-benzyloxy)-3-nitrophenyl) ethanol (2)

Cis-(1R,2S)-aminoindanol (0.2 eq.)was reacted with trimethylboroxine(0.07 eq.) in toluene to give oxazaborolidine. After azeotropic removalof methaneboronic acid, THF and borane (0.2 eq.) were added followed bysimultaneous addition of more borane (0.7 eq.) and a solution ofbromoketone 2-bromo 4'-benzyloxy-3'-nitroacetophenone (1 eq.) intetrahydrofuran at -15° C. The product (R)-bromohydrin was isolated byextraction from aqueous acid in >98% yield (ee=95%).

EXAMPLE 3 4-Benzyloxy-3-nitrostyrene oxide (1)

If it is desired to isolate the epoxide, as opposed to generating it insitu in the next step, the following procedure may be used: A solutionof the R-enantiomer of 2 (16.0 g, 45 mmol, ee=99.9%) in THF (100 mL) andmethanol (100 mL) was stirred in the presence of potassium carbonate(8.3 g) for 2 hours. The reaction mixture was concentrated and thenextracted with ethyl acetate (200 mL) and water (100 mL). The organiclayer was dried over Na₂ SO₄, filtered and concentrated leaving 12.0 g(97%) of 1 as an orange solid.

EXAMPLE 4(R,R)-2-Benzyloxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-1-nitrobenzene (5)

Epoxide 1 (10.6 g, 39 mmol) was reacted with the R-enantiomer ofbenzylamine 4 (10.0 g, 30 mmol) under argon at 90° C. for 15 hours. Thereaction mixture was purified by column chromatography usingEtOAc/hexanes (1:2) to give 15 g of 5 as an orange oil in 73% yield.

EXAMPLE 5 (R,R)-3-amino-4-hydroxy-α-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl]- benzenemethanol(R,R)-Desformoterol

The R,R-enantiomer of dibenzyldesformoterol 5 (6.9 g, 13 mmol) wasreacted with L-tartaric acid (2.0 g, 13 mmol) in MeOH (5 mL). Themixture was heated to 60° C. and a clear solution was obtained. Thesolution was concentrated to dryness to leave 9.0 g of the tartrate saltof the R,R-enantiomer of 5 as a yellow powder. This material (2.2 g) washydrogenated at 50 psi in 30 mL MeOH in the presence of Pd-C (Degussatype NE/W, 10% Pd, 0.4 g). The reaction mixture was filtered throughCelite, washed with 60 mL CH₃ CN and concentrated to dryness leaving 1.0g (75%) of (R,R)-desformoterol-L-tartrate as an off-white powder.

EXAMPLE 6 4-Methoxy-α-methyl-N-(phenylmethyl)benzene ethaneamineL-mandelic acid salt (3)

To 800 mL of methanol were added 328 g of 4-methoxyphenylacetone (2 mol)and 214 g of N-benzylamine (2 mol). The imine formation was exothermicand the solution warmed to 45° C. After reaction was complete, thesolution was hydrogenated at 50 psi for 6-8 hours in the presence of 3.3g of 5% platinum on carbon catalyst. When the hydrogen uptake hadstopped, the reaction was filtered through diatomaceous earth, and thefilter cake was washed with 200 mL of methanol. The combined filtrateswere placed in a 6-liter flask and diluted with 4.2 liters of methanol.(S)-L-Mandelic acid (304 g, 2 mol) was added and the mixture heated withstirring to reflux to obtain a clear solution. The solution was cooledto room temperature, stirred at room temperature for two hours and themandelic acid salt filtered off. The recrystallization was repeatedthree times to obtain 60-70 g of the mandelic acid salt of the benzylamine having an isomeric purity greater than 99.8% and a melting pointof 164° C.

EXAMPLE 7 Formula for Oral Inhalation

    ______________________________________                                                         Quantity contained in Each                                     Formula Metered Dose Dispenser                                              ______________________________________                                        (R,R,)-desformoterol tartrate                                                                        1.8    mg                                                trichloromonofluoromethane 5.16 g                                             dichlorodifluoromethane 5.16 g                                                sorbitan trioleate 0.105 g                                                  ______________________________________                                    

The metered dose dispenser contains micronized (R,R)-desformoteroltartrate in suspension. Each actuation delivers 6μ of(R,R)-desformoterol tartrate from the mouthpiece. Each canister providesabout 300 inhalations.

EXAMPLE 8 Oral Formulation

    ______________________________________                                                         Quantity per                                                   Tablet (mg.)                                                                Formula            A        B                                                 ______________________________________                                        (R,R)-desformoterol tartrate                                                                     0.12           0.25                                          Lactose 41.38  41.25                                                          Cornstarch 3.0  3.0                                                           Water (per thousand Tablets)* 30.0 ml 30.0 ml                                 Cornstarch 5.00  5.00                                                         Magnesium Stearate 0.50  0.50                                                  50.00  50.00                                                               ______________________________________                                         *The water evaporates during manufacture.                                

The desformoterol is mixed with the lactose until a uniform blend isformed. The smaller quantity of cornstarch is blended with the water toform a cornstarch paste. The paste is then mixed with the lactose blenduntil a uniform wet mass is formed. The remaining cornstarch is added tothe resulting wet mass and mixed until uniform granules are obtained.The granules are then screened through a suitable milling machine, usinga 1/4 inch stainless steel screen. The milled granules are then dried ina suitable drying oven until the desired moisture content is obtained.The dried granules are then milled through a suitable milling machine,using 1/4 mesh stainless steel screen. The magnesium stearate is thenblended and the resulting mixture is compressed into tablets of desiredshape, thickness, hardness and disintegration.

I claim:
 1. A process for preparing a compound of formula ##STR19##comprising the sequential steps of: (a) providing a compound of formula;##STR20## and (b) reducing said compound.
 2. A process according toclaim 1, wherein the compound of formula: ##STR21## is prepared byreacting a compound of formula ##STR22## with a compound of formula##STR23## wherein R is benzyl or substituted benzyl.
 3. A process forpreparing a salt of a compound of formula ##STR24## comprising thesequential steps of: (a) providing a compound of formula; ##STR25## and(b) reducing said compound in the presence of an acid.
 4. A processaccording to claim 3, wherein the compound of formula ##STR26## isprepared by reacting a compound of formula ##STR27## with a compound offormula ##STR28## wherein R is benzyl or substituted benzyl.
 5. Aprocess according to claim 1 or 3, wherein said reducing step is carriedout with a source of hydrogen in the presence of a noble metal catalyst.6. A process according to claim 5, wherein said noble metal catalyst ispalladium.
 7. A process according to claim 3, wherein said salt is atartrate salt, and wherein said reducing step is carried out with asource of hydrogen in the presence of a noble metal catalyst andtartaric acid.
 8. A process according to claim 3 wherein said compoundof formula ##STR29## is of the R,R configuration.
 9. A process accordingto claim 3 wherein said compound of formula ##STR30## is of the S,Sconfiguration.
 10. A process according to claim 3 wherein said compoundof formula ##STR31## is of the R,S configuration.
 11. A processaccording to claim 3 wherein said compound of formula ##STR32## is ofthe S,R configuration.
 12. A method of inducing bronchodilation orpreventing bronchoconstriction comprising administering to an individuala therapeutically effective quantity of desformoterol, or apharmaceutically acceptable salt thereof.
 13. The method of claim 12wherein desformoterol is administered orally or by subcutaneousinjection, intravenous infusion, inhalation, or transdermal delivery.14. A method according to claim 13 wherein desformoterol is administeredorally.
 15. A method according to claim 13, wherein said desformoterolis administered by inhalation.
 16. The method according to claim 15,wherein the amount administered by inhalation is about 1 μg to about 100μg per day.
 17. The method of claim 12, wherein racemic desformoterol,or a pharmaceutically acceptable salt thereof, is administered.
 18. Themethod of claim 12, wherein R,R-desformoterol, or a pharmaceuticallyacceptable salt thereof, is administered.
 19. The method of claim 12,wherein R,S-desformoterol, or a pharmaceutically acceptable saltthereof, is administered.
 20. A pharmaceutical composition comprising apharmaceutically acceptable carrier and desformoterol, or apharmaceutically suitable salt thereof.
 21. A pharmaceutical compositionaccording to claim 20 comprising racemic desformoterol, or apharmaceutically suitable salt thereof, and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition according to claim20 comprising (R,R)-desformoterol, or a pharmaceutically suitable saltthereof, and a pharmaceutically acceptable carrier.
 23. A pharmaceuticalcomposition according to claim 20 in the form of an aerosol formulation,wherein said pharmaceutically acceptable carrier comprises a propellant.24. A pharmaceutical composition according to claim 20 for oraladministration.
 25. A pharmaceutical composition according to claim 24in the form of a syrup.
 26. A pharmaceutical composition according toclaim 24 in the form of a tablet or a capsule.
 27. A pharmaceuticalcomposition according to claim 26 in sustained release form. 28.R,R-desformoterol or a pharmaceutically acceptable salt. 29.S,S-desformoterol or a pharmaceutically acceptable salt. 30.R,S-desformoterol or a pharmaceutically acceptable salt. 31.S,R-desformoterol or a pharmaceutically acceptable salt.